Psychiatric and neurologic disorders are among the most severe and chronic diseases and conditions. These disorders are also extremely difficult to treat effectively because of the multiplicity of the symptoms and etiologies.
Amongst the therapeutic arsenal to combat these psychiatric and neurologic disorders, sigma receptors inhibitors have been found useful in the treatment of psychosis and movement disorders such as dystonia and tardive dyskinesia, and motor disturbances associated with Huntington's chorea or Tourette's syndrome and in Parkinson's disease (Walker, J. M. et al, Pharmacological Reviews, 1990, 42, 355).
WO2006021462 and WO2007098953 describe pyrazole-containing compounds having pharmacological activity towards the sigma receptor, being particularly useful in the therapy of pain, in particular neuropathic pain or allodynia. These compounds have the following chemical structure:

These compounds may be prepared according to the route schemes disclosed in WO2006021462 and WO2007098953. Of particular interest are the intermediates represented by the formula (II) in said patent applications (further referred as final intermediates):
wherein R3 and R4 are independently halogen or C1-6alkoxy, or together with the phenyl to which they are attached to, they form an optionally substituted naphthyl ring.
According to the routes presented in the mentioned patent applications, these intermediates can be prepared by reacting an acetohydrazide derivative with an ethyl acetoacetate; by reacting an hydrazine derivative with an ethyl butynoate; or by the method provided by F. Effenberger and W. Hartmann, Chem. Ber., 102(10), 3260-3267, 1969, where an ethoxy-acrylic acid hydrazide is reacted with concentrated mineral acid.
When considering different routes for the preparation of the 1-aryl-pyrazol-3-one intermediates referred above, one approach is to directly react an arylhydrazine with a ketoacetate. However, this shortcut presents the drawback that being the distal nitrogen of hydrazine the most reactive atom, it will preferably react with the ketone carbonyl of ketoacetate—more electrophilic—rather than with the ester carbonyl of the same reagent, as it would be desired. The non-desired reaction results in an enamine that after cyclization yields the non-desired isomer of 1-aryl-pyrazol-3-one intermediates, i.e. 1-aryl-pyrazol-5-one (depicted below). This reaction was reproduced by the inventors and it is also described in Bioor. and Med. Chem. 2004, 2317.

As such, because of this undesired reaction, the solution proposed by WO2006021462 and WO2007098953, protects the arylhydrazine by converting it into an acetohydrazide, thereby forcing a reaction between the proximal nitrogen atom of the hydrazide—now more reactive—with the ketone carbonyl of ethyl acetoacetate. An enamine is formed, which is submitted to energetic acidic conditions in order to be cyclised and thereby results into the 1-aryl-pyrazol-3-one intermediate. Such energetic conditions generate a significant amount of by-products that consequently diminish the reaction yield.
WO2009130314 (Laboratorios del Dr. Esteve) relates to a process for preparing naphthalen-2-yl-pyrazol-3-one intermediates, tautomers, and salts thereof, to novel intermediates, and to the use of the intermediates in the preparation of sigma receptor inhibitors. This alternative route comprises in particular submitting 2-methyl-2-(naphthalen-2-yldiazenyl)furan-3(2H)-ones to acidic conditions.
Ueda et al. (Synthesis of pyrazolone derivatives. XLII. Synthesis and analgesic activity of 2-methyl-1-phenyl-6,7-dihydro-1H,5H-pyrazolo[5,1-b][1,3]oxazin-8-ium bromide. Yakugaku Zasshi (1982), 102(8), 743-7) proposes in Chart I of page 744 and in the last two paragraphs on page 745, the reaction of an ethyl 2-(2-methyl-1,3-dioxolan-2-yl)acetate with phenylhydrazine in the presence of sodium methoxide as a base and benzene as a solvent, thereby obtaining 2-(2-methyl-1,3-dioxolan-2-yl)-N′-phenylacetohydrazide, which is further cyclised after treatment with hydrochloric acid 10% and heating on a water bath at 90° C., to obtain 3-hydroxy-5-methyl-1-phenylpyrazole. However, this method presents the disadvantage that both sodium methoxide and benzene are unsuitable for industrial upscaling, in particular, sodium methoxide is a dangerous and highly toxic reagent and benzene is carcinogenic and therefore unsuitable for use in large quantities. Moreover, the reaction devised by Ueda et al. presents a non-optimal yield for 2-(2-methyl-1,3-dioxolan-2-yl)-N′-phenylacetohydrazide (30%). Most importantly, when the inventors tried to reproduce said reaction with similar conditions and a naphthylhydrazine was used instead of the phenylhydrazine (see Example 26 below), they were unsuccessful in preparing the desired final intermediate in optimal isomeric purity. Adversely, an isomeric mixture (80:20) of 5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-ol (desired isomer) and 3-methyl-1-(naphthalen-2-yl)-1H-pyrazol-5-ol (non-desired isomer) was obtained. This process does not avoid the distal nitrogen of the hydrazine from reacting with the ketone carbonyl of the ketoacetate, thereby generating by-products that make this route not interesting for industrial production.
As such, the inventors confronted with the problems on the control of the regioselectivity of the mentioned reaction, and trying to meet the need for an improved and industrially feasible process when compared to the ones proposed by WO2006021462, WO2007098953, WO2009130314, and Ueda et al., they have envisaged a regioselective process where the ketoacetate is replaced by a more advantageous reagent—the acid form—and have surprisingly found that said process not only works and results in an increased yield versus the prior art processes, but it also allows the industrial production of these intermediates with, most importantly, a high degree of isomeric purity.